Current Medicinal Chemistry - Online First

Glioblastoma is the most common and aggressive brain tumor, with low survival rates and high recurrence rates. Therefore, it is crucial to understand the precise molecular mechanisms involved in the oncogenesis of glioblastoma.

To investigate the regulatory mechanisms of long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (miRNA) network related to glioblastoma, in the present study, a comprehensive analysis of the genomic landscape between glioblastoma and normal brain tissues from the Gene Expression Omnibus (GEO) dataset was first conducted to identify differentially expressed genes (DEGs) in glioblastoma. Following a series of analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, protein-protein interaction (PPI), and key model analyses. In addition, we used the L1000CDS2 database bioinformatic tool to identify candidates for therapy based on glioblastoma specific genetic profile.

In our results, 100 key genes, 50 upregulated and 50 downregulated, were ultimately identified. The results of KEGG pathway enrichment gene analysis showed that the five regulatory pathways. Furthermore, 3 small molecule signatures (trichostatin A, TG-101348, and vorinostat) were recommended as the top-ranked candidate therapeutic agents. Nevertheless, the constructed miRNA-mRNA network revealed a convergence on 40 miRNAs. We found that dysregulation of lncRNAs such as KCNQ1OT1 and RP11-13N13.5 could sequester several miRNAs such as hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-106a-5p, etc., and promote the development and progression of glioblastoma.

Our study identified key genes and related lncRNA-miRNA-mRNA network that contribute to the oncogenesis of glioblastoma.

Over 85% of biologically active compounds are heterocycles or contain heterocyclic groups, underscoring their vital importance in contemporary drug development. Among them, nitrogen-containing derivatives, such as pyridines and pyrimidines, are considered privileged structures in approved drugs or are extensively studied due to their promising therapeutic effects.

In the current work, we would like to verify the hypothesis that incorporating heterocyclic pharmacophores into derivatives of pyrimidine-2(1H)-thione (PMT), 2-pyridone (P), pyridine-2(1H)-thione (PT), dihydropyrimidine-2(1H)-thione (DHPMT), dihydropyridin-2(1H)-one (DHP), and dihydropyridine-2(1H)-thione (DHPT) rings enhances antitumor activity.

A range of novel pyridine- and pyrimidine-based compounds were synthesized and assessed for their anticancer properties against the melanoma A375 cell line. The two most potent compounds (16b and 29) were then chosen for further evaluation of their effects on non-cancerous human dermal fibroblasts, cancer cell apoptosis, cell cycle phase distribution, and tubulin polymerization. Furthermore, in silico analyses were performed to assess the pharmacokinetics, toxicity, drug-likeness, and molecular target of the selected compounds.

Among the 33 compounds tested, pyridine analogs 16b and 29 demonstrated the strongest antiproliferative activity (with IC50 values of 1.85 ± 0.44 µM and 4.85 ± 1.67 µM, respectively) and selectivity (SI=65.08 and SI> 100, respectively) against cancer cells. Additional studies revealed that compound 16b, which features a thiophene ring at the C-5 position and a 3,4,5-trimethoxyphenyl (TMP) group, showed the most promising cell cycle arrest and tubulin polymerization inhibition (IC50=37.26 ± 10.86 µM), resulting in cancer cell apoptosis. In silico ADMET analysis confirmed the drug- likeness of the synthesized compounds.

This research reinforced the significance of heterocyclic rings as valuable pharmacophores. Additionally, it highlighted the antiproliferative and antimitotic potential of modified pyridine derivatives.

This study investigated the causes of Mitochondrial Dysfunction (MD) in Diabetic Kidney Disease (DKD) progression, and identified genes associated with DKD, especially those with significant genetic causal effects, to provide a theoretical basis for DKD treatment.

Using a large database and single-cell RNA sequencing (scRNA-seq) data, 333 MDRDEGs were discovered. MDRDEGs were linked to AGE-RAGE signaling, RNA processing, protein transport, and energy metabolism using functional enrichment analysis. Seven MDRDEGs with significant genetic causal effects in DKD were discovered using SMR and MR analyses: ACTN1, ALG11, CCNB1, HIVEP2, MANBA, TUBA1A, and WFS1. Co-localization and scRNA-seq analyses examined these genes' DKD connections. Due to the high significance of its prediction model and DKD expression, ACTN1 was studied in depth. PheWAS and molecular dynamics analysis assessed ACTN1's safety and efficacy as a therapeutic target, and its connection with other symptoms. ACTN1 protein expression in DKD tissues was confirmed by immunofluorescence.

Functional enrichment analysis revealed that MDRDEGs were mostly related to AGE-RAGE signaling, RNA processing, protein transport, and energy metabolism. Seven MDRDEGs caused DKD genetically in SMR and MR investigations. Genetic variations in ACTN1, ALG11, MANBA, and TUBA1A were linked to DKD by co-localization studies. scRNA-seq showed a dramatic increase in ACTN1 expression in DKD. Molecular dynamics analysis demonstrated that Dihydroergocristine can safely bind to ACTN1, while the PheWAS investigation found no significant relationships. DKD tissues exhibited higher ACTN1 protein levels via immunofluorescence.

This study identified MDRDEGs linked to inflammation, cytoskeletal stabilization, and glucose metabolism pathways critical in Diabetic Kidney Disease (DKD) pathogenesis, highlighting their clinical potential as therapeutic targets. Notably, ACTN1 emerged as a causally linked gene overexpressed in DKD, with the prediction of dihydroergocristine as a targeting compound, offering novel avenues for clinical intervention.

This study suggests that ACTN1 may be a therapeutic target for DKD and sheds light on its molecular pathogenesis, clinical prevention, and treatment.

Endothelial dysfunction is the altered pathological ability of endothelial cells to modulate the passage of cells and solutes across vessels, which underlies the development of inflammatory diseases. Betanin (betanidin-5-O-β-glucoside), a natural product rich in red beets, is a water-soluble nitrogen-containing pigment, and its potential protective effects on cardiovascular disease have been reported. In this study, we investigated the protective role of betanin in vascular endothelial dysfunction induced by TNFα and explored potential mechanisms.

We modelled endothelial dysfunction through TNFα stimulation in human umbilical vein endothelial cells (HUVECs) and examined the role of betanin and its possible mechanism of action by MTT assay, Western blotting, and immunofluorescence staining. A systemic inflammation model of mice was built through LPS to investigate the protective roles of betanin.

Betanin pre-treatment increased cell viability, inhibited the expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and improved endothelial tight junction by upregulating the expression of occludin and zonula occludens-1 (ZO-1) after TNFα stimulation in HUVECs. In terms of endothelial-mesenchymal transition, betanin up-regulated the expression of endothelial phenotypes VE-cadherin and CD31, whereas it inhibited the expression of mesenchymal phenotype N-cadherin, indicating that betanin reduced endothelial-mesenchymal transition in TNFα-stimulated HUVECs. In addition, betanin increased the expression of LC3 and decreased the expression of p62, two central proteins in autophagy. Betanin also reversed the abnormal autophagic flux after TNFα exposure. However, the specific autophagy inhibitor, 3-methyladenine, blocked the protective effect of betanin. Finally, betanin was found to greatly decrease ICAM-1 and VCAM-1 expression, and upregulate occludin and ZO-1 levels in a systemic inflammation model of mice.

The above results collectively suggested that betanin may improve endothelial dysfunction by promoting autophagy, thus exerting beneficial effects on cardiovascular health.

Negative emotional states, such as nervousness, anxiety, depression, and tension, exert profound detrimental effects on an individual's quality of life and overall health. Although certain widely prescribed medications have been observed to modulate these emotional states, the existing body of research in this domain remains insufficient. To address this gap, Mendelian randomization (MR) methodologies, leveraging large-scale datasets, were employed to investigate the causal relationships between 21 commonly utilized medications and the manifestation of negative emotions.

The inverse variance weighting (IVW) method was employed as the primary analytical strategy to analyze causal relationships. MR-Egger, weighted mode, and weighted median approaches were utilized to enhance the robustness of the results. Sensitivity analyses were conducted to assess the stability of the data.

Agents acting on the renin-angiotensin system, β-blocking agents, antithrombotic agents, and salicylic acid and derivatives could reduce the risk of nervousness, anxiety, tension, or depression (OR = 0.61, 95% CI 0.37 to 0.99, p = 0.047; OR = 0.59, 95% CI 0.36 to 0.98, p = 0.041; OR = 0.55, 95% CI 0.34 to 0.88, p = 0.013; OR = 0.61, 95% CI 0.40 to 0.95, p = 0.030), with no heterogeneity, horizontal pleiotropy, or reverse causation (p > 0.05).

This study revealed four medications associated with reducing the risk of negative emotions, providing clinicians with a scientific basis for medication selection to better assist patients in alleviating psychological issues and improving their quality of life.

The purpose of this study is to construct and validate a neuroendocrine differentiation-related molecular model for predicting prognosis in patients with prostate cancer (PCa).

Transcriptome data for PCa were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) websites. Differentially expressed neuroendocrine differentiation related genes (NDGs) were identified. By utilizing multivariate Cox analysis, a neuroendocrine differentiation-related molecular model for predicting prognosis was constructed and validated. The study investigated the novel model’s association with the tumor immune microenvironment, clinicopathological characteristics, tumor stemness, and anticancer treatment sensitivity. Additionally, preliminary experimental verifications of Diencephalon / Mesencephalon Homeobox 1 (DMBX1) were conducted.

Finally, we identified a total of 19 differentially expressed NDGs. A neuroendocrine differentiation-related molecular model was established and successfully validated both internally and externally. The high-risk group   exhibited   significantly   poorer biochemical recurrence-free survival (BCRFS) in the training, testing, and validating cohorts. The areas under the receiver operating characteristic curves for the training, testing, and validating cohorts were 0.825, 0.719, and 0.729, respectively. The tumor immune microenvironment, clinicopathological features, tumor stemness, and anti-cancer drug sensitivity was significantly different between high and low-risk patients. Preliminary experiments revealed that higher expression of DMBX1 significantly enhanced the proliferation, migration, and neuroendocrine differentiation of PCa cells.

This research developed a unique neuroendocrine differentiation-related molecular model that is highly suitable for predicting BCRFS. High DMBX1 expression may promote the development and neuroendocrine differentiation of prostate cancer.

Icaritin is a bioactive flavonol isolated from the Chinese medicinal herb Epimedium. The comprehensive understanding of antifibrotic effects and associated molecular mechanisms of icaritin remains incomplete. This study aims to explore the protective effects of icaritin against liver fibrosis and to further elucidate the mechanisms involved.

Human hepatic stellate LX-2 cells stimulated with TGF-β1 and a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model were employed. In vitro assays were carried out to evaluate collagen type I (COL I) and α-smooth muscle actin (α-SMA) expression, while in vivo studies assessed fibrosis alleviation. Molecular mechanisms were explored via analysis of TGF-β1, phosphorylated Smad2/3, and HIF-1α protein levels using Western blotting.

Icaritin suppressed TGF-β1-induced COL I and α-SMA expression in LX-2 cells and ameliorated liver fibrosis in CCl4-treated mice. Mechanistically, it significantly reduced TGF-β1 levels, inhibited Smad2/3 phosphorylation, and downregulated HIF-1α protein expression in LX-2 cells.

Icaritin attenuated experimental liver fibrosis through the inhibition of the TGF-β/Smad and HIF-1α signaling pathways, highlighting its therapeutic potential for fibrotic liver diseases.